Billirubin Metabolism

By: Taufiq RN

The Concept of Jaundice

Jaundice
Elevation of billirubin in the plasma

Overproduction of
Billirubin
Hemolytic anemias

Exretion failure of
Billirubin
Hepatitis
pancreas cancer

Human & Animal Hemoprotein

(protein that contain heme)
Protein

Function

Hemoglobin

Transport oxygen in blood

Myoglobin

Storage oxygen in muscle

Cytochrome C

Involvement in electron
transport chain

Cytochrome p450

Hydroxylation of xenobiotics

Catalase

Degradation of hydrogen
peroxide

Tryptophan
pyrolase

Oxidation of tryptophan

Catabolism of Heme Produce Bilirubin

In the human adult 1 2 x 108

erythrocytes are destroyed per
hour
In one day, a 70 kg human turn
over + 6 gr of hemoglobin
When hemoglobin is destroyed,
globin is degraded to its
constituent aminoacids and iron
for reuse
Free iron porphyrin also degrade,
mainly in reticulo endothelial cells
of the liver, spleen, and bone
marrow

The catabolism of heme is carried

out in the microsomal fraction of
cells by a complex enzyme
system called heme oxygenase

Its estimated that each 1 gr of

hemoglobin yield 35 mg of
bilirubin
The daily bilirubin formation in human
adult is + 250 350 mg, deriving
from Hb, in efective erythropoisis,
and cytochrome P450

Bilirubin formed in peripheral

tissues is transported to the
liver by plasma albumin and
further metabolized by liver
The Bilirubin metabolism process can
be divided into three step:
1. uptake bilirubin by parenchymal
liver cells
2. Conjugation of bil with glucoronate
in the endoplasmic reticulum
3. Secretion of conjugated bil into the
bile

BLOODBilirubin + Albumin
UPTAKE

HEPATOCYTES
Bilirubin
UDP GlcUA
UDP GlcUA

CONJUGATION

Bilirubin diglucoronide

SECRETION
Bilirubin diglucoronide
HEPATOCYTES

Billirubin Uptaken by Liver

One hight affinity side One low
affinity side
25 mg tightly bound/100ml
Plasma; more loosely bound
Antibiotics and other drugs can
compate with bilirubin for the
high-affinity binding side of
albumin
Bilirubin removed from albumin
mediated by facilitated transport
system
Once bilirubin enter hypatocytes ,
it can bind cytosolic protein
(ligandin; glutathion transferase
family)
Prevent efflux of bilirubin back into
the blood stream

Bilirubin conjugation
UDP glucose
UDP
dehydrogenase
UDP
Glucoronic
glucose
aciddehydrog
Readily excreted in the
enase
bile by adding glucoronic
+2NADH + 2H+
2NAD

Hepatocytes convert
bilirubin to polar form

acid (conjugation)
UDP glucoronosyl
bilirubin
Bil
transferase
UDP
monoglucoronide
monoglucoro
glucor ac
nid + UDP
bilirubin diglucoronide
(mostly excreted in bile) + bil

UDP glucoronosyl
Bil
Enzyme that needed at
transferase
UDP
diglucoronid
the reaction is
glucor ac
+ UDP
glucoronyl transferase + bil monogluc

(located in ER)

Bilirubin is Screted into Bile

By active transport
(rate limiting)
MRP-2 (multidrugresistance like
protein-2) = MOAT
(multispecific organ
anion transporter)
located in
membrane of bile
canalicular a
member ATP
binding cassete
family transporter

Conjugated Bilirubin is reduced by

Bacteria in Intestinal
Glucoronide are removed by
Beta glucoronidase (bacterial
enzyme) urobilinogen
(colourless)
Urobilinogen is partly
reabsorbed and reexcreted
through the liver
(enterohepatic urobilinogen
cycle)
Normally urobilinogen are
oxidized to urobilin (colored)
and excreted in faeces
Darkening of faeces upon
standing in air is due to the
oxidation of residual
urobilinogens to urobilins

Jaundice

When bilirubin in blood more than 1 mg/dl

(17.1 mol/L) hyperbilirubinemia
When concentration of bilirubin exceeds 2 2.5
mg/dl, can diffuse into the tissues, which then
become yellow (jaundice)

There are two types of hyperbilirubinemia

Retention hyperbilirubinemia
Unconjugated (hydrophobicity) can cross blood
brain barier encephalopathy. Larut dlm lemak.
Terikat oloeh albumin. B1. indirek. BERBAHAYA
Acholuric jaundice only occur in this type of
hyperbilirubinemia

Regurgitation hypergbilirubinemia
Conjugated bilirubin (water solubility), can appear in
urine. Terikat oleh as. Glukoronat. Larut dlm air. B2.
direk